Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase

Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS

Natural durability of five tropical wood species in field decay tests

Measuring the natural resistance of wood is fundamental for proper use. The natural durability of five tropical wood species was investigated by field decay testing during exposure for 360 days. Wood logs (length of 0,5 m; diameter of 8 cm - 12 cm) were used in this study. The mass loss and decay index were calculated and visual analysis during the exposure time was performed for all samples. The samples presented evidence of two different groups concerning natural durability. The species in the first group (Mimosa caesalpiniifolia, Mimosa ophthalmocentra, and Mimosa tenuiflora) showed the highest resistance to biodeterioration, better or similar performance compared to treated eucalyptus wood (as control). The other group (Aspidosperma pyrifolium and Cordia oncocalyx) had lower natural resistance in outdoor service, being more susceptible to decay. In general, the wood of the first group is indicated for outdoor uses that require medium or prolonged exposure, such as timber stakes and fence posts

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra‐high field MRI and diffusion tensor metrics

bjective: Cell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the useof diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS.Methods: Ultra-high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A-SOD1) mice.Results: Changes in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (CL, CP, and CS, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, CL, and CP values decreased, whereas CS values increased.In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL a nd C values were unchanged or slightly smaller.Histological studies of a fluorescent mice model (YFP, G93A-SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI.Conclusions: Changes in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of CL, CP, and CSas imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALSFil: Gatto, Rodolfo G.. University Of Illinois. Deparment Of Biological Science; Estados UnidosFil: Weissmann, Carina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Amin, Manish. University of Florida; Estados UnidosFil: Finkielsztein, Ariel. Northwestern University; Estados UnidosFil: Sumagin, Ronen. Northwestern University; Estados UnidosFil: Mareci, Thomas H.. University of Florida; Estados UnidosFil: Uchitel, Osvaldo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Magin, Richard L.. University Of Illinois. Deparment Of Biological Science; Estados Unido

Recent Advances in Liquid Biopsy in Patients With Castration Resistant Prostate Cancer

Management of localized and advanced prostate cancer benefits from several therapeutic options with a surprising improvement in terms of clinical outcome. The selection of patients more likely to benefit from a specific approach still remains a key issue as well as the early identification of patients with aggressive disease which could benefit from a more aggressive treatment strategy. The lack of reliable bio-marker in castration resistant setting able to monitor response to treatment and early inform about tumor progression is an emerging issue. Accordingly, circulating DNA and circulating tumor cells appears a promising and attractive approach despite to date practical applications of these techniques are few and not validated. The aim of this review of the literature is to explore current knowledge on liquid biopsy in prostate cancer focusing on possible future applications

Resistance to Systemic Agents in Renal Cell Carcinoma Predict and Overcome Genomic Strategies Adopted by Tumor

The development of new systemic agents has led us into a “golden era” of management of metastatic renal cell carcinoma (RCC). Certainly, the approval of immune-checkpoint inhibitors and the combination of these with targeted compounds has irreversibly changed clinical scenarios. A deeper knowledge of the molecular mechanisms that correlate with tumor development and progression has made this revolution possible. In this amazing era, novel challenges are awaiting us in the clinical management of metastatic RCC. Of these, the development of reliable criteria which are able to predict tumor response to treatment or primary and acquired resistance to systemic treatments still remain an unmet clinical need. Thanks to the availability of data provided by studies evaluating genomic assessments of the disease, this goal may no longer be out of reach. In this review, we summarize current knowledge about genomic alterations related to primary and secondary resistance to target therapy and immune-checkpoint inhibitors in RC

ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 115, doi:10.1038/s41598-017-00091-1.Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.We are grateful for funding from NIH/NINDS (R01 NS078145, R01 NS090352, and R21 NS091860 to D.A.B., R01 NS066942A and R21 NS096642 to G.M., R01NS023868 and R01NS041170 to S.T.B.), the ALS Therapy Alliance/CVS Pharmacy (to D.A.B. and G.M.) and the ALS Association (to C.F. and J.M.)

USE OF SOLAR KILN FOR THE DRYING OF SAWN WOOD

RESUMO O objetivo desse estudo foi avaliar o uso da estufa solar para secagem das madeiras de Eucalyptus tereticornis, Eucalyptus saligna e Corymbia citriodora, bem como comparar essa metodologia com a secagem ao ar livre. Para tanto, foi desenvolvido um secador solar constituído por estruturas de madeira, cobertura com dupla camada de plástico PVC (policloreto de vinila), sistema coletor interno de energia solar e sistema de circulação do ar aquecido. A eficiência do secador solar foi comparada com a secagem ao ar livre quanto ao tempo de secagem e qualidade da madeira. Cada espécie foi submetida, no mesmo período, aos dois métodos de secagem, sendo utilizadas cargas com 55 tábuas em cada método. Os resultados obtidos indicaram que a estufa solar foi mais eficiente apresentando tempo de secagem de duas a cinco vezes menores que a secagem ao ar livre e com teor de umidade final mais baixo. A madeira seca, tanto na estufa solar quanto ao ar livre, apresentou boa qualidade, não sendo verificada a incidência de defeitos como encanoamento e colapso. Além disso, o correto empilhamento e a tecnologia de secagem utilizados proporcionaram poucos empenos do tipo encurvamento. A incidência de arqueamentos, rachaduras de superfície e de topo não apresentaram diferença significativa entre a secagem em estufa solar e ao ar livre para as três madeiras estudadas.ABSTRACT This study aimed at evaluating the use of a solar kiln for the drying of woods of Eucalyptus tereticornis, Eucalyptus saligna and Corymbia citriodora, as well as comparing such a methodology to the air seasoning practice. In order to do so, it was built a solar kiln composed basically of wood structures, roofing with a double layer of PVC, sunlight internal collector and hot air circulation systems. The efficiency of the solar kiln was compared to the air seasoning in drying time and wood quality. In the same drying schedule, each species was submitted to the two drying approaches using a load of 55 boards in each method. Results indicated that the solar kiln was more efficient in drying time, around 2 to 5 times faster and final moisture content lower than the air drying. Adequate wood quality was observed in both drying methods, and no defects such as cup or collapse were observed. Furthermore, the correct piling up and drying process provided minimization of defects such as bow. The incidence of crook, end and surface checks were not significantly distinct between solar drying and air seasoning for the three woods studied

Durabilidade natural da madeira de três espécies florestais em ensaios de campo.

This work aimed to evaluate the natural durability of heartwood and sapwood of Luhea divaricata, Carya illinoinensis and Platanus x acerifolia. Test samples measuring 2.5 x 2.5 x 30.0 cm (radial x tangential x longitudinal) were placed in a pine forest stand and an open field. During a year, the samples were repeatedly weighed and evaluated by a rating system to determine mass loss and decay index, respectively. The results showed that regardless of species and type of wood, the forest environment is more favourable to decay than that of the open field. Despite the high correlation between mass loss and decay index, variations in the durability of wood were found between these parameters. The wood from the internal section of the log (sapwood) was the more affected. For mass loss, no significant variation was observed for the species analyzed, however, for the decay index Platanus x acerifolia was shown to be the most affected.Com o objetivo de avaliar a durabilidade natural da madeira, amostras de alburno e de cerne de Luehea divaricata (açoita-cavalo), Carya illinoinensis (nogueira-pecã) e Platanus x acerifolia (plátano), medindo 2,5 x 2,5 x 30,0 cm (radial x tangencial x longitudinal), foram submetidas a ensaios experimentais em um povoamento de Pinus e em campo aberto. Durante um ano, as amostras foram periodicamente pesadas e avaliadas pelo critério de notas, para determinar o percentual de perda de massa e índice de deterioração, respectivamente. Os resultados mostraram que, independente da espécie e do tipo de lenho, o ambiente dentro da floresta é mais favorável a deterioração da madeira do que fora dele. Apesar da elevada correlações entre a perda de massa e o índice de deterioração foram observadas variações na avaliação da durabilidade da madeira entre esses critérios. Para todas as espécies, a madeira proveniente do alburno foi a mais atacada. Para perda de massa não foi observada diferença entre as espécies avaliadas, entretanto, o índice de deterioração apontou o plátano como a mais atacada

Natural Durability Of Three Wood Species In Field Tests

Com o objetivo de avaliar a durabilidade natural da madeira, amostras de alburno e de cerne de Luehea divaricata (a\ue7oita-cavalo), Carya illinoinensis (nogueira-pec\ue3) e Platanus x acerifolia (pl\ue1tano), medindo 2,5 x 2,5 x 30,0 cm (radial x tangencial x longitudinal), foram submetidas a ensaios experimentais em um povoamento de Pinus e em campo aberto. Durante um ano, as amostras foram periodicamente pesadas e avaliadas pelo crit\ue9rio de notas, para determinar o percentual de perda de massa e \uedndice de deteriora\ue7\ue3o, respectivamente. Os resultados mostraram que, independente da esp\ue9cie e do tipo de lenho, o ambiente dentro da floresta \ue9 mais favor\ue1vel a deteriora\ue7\ue3o da madeira do que fora dele. Apesar da elevada correla\ue7\uf5es entre a perda de massa e o \uedndice de deteriora\ue7\ue3o foram observadas varia\ue7\uf5es na avalia\ue7\ue3o da durabilidade da madeira entre esses crit\ue9rios. Para todas as esp\ue9cies, a madeira proveniente do alburno foi a mais atacada. Para perda de massa n\ue3o foi observada diferen\ue7a entre as esp\ue9cies avaliadas, entretanto, o \uedndice de deteriora\ue7\ue3o apontou o pl\ue1tano como a mais atacada.This work aimed to evaluate the natural durability of heartwood and sapwood of Luehea divaricata , Carya illinoinensis and Platanus x acerifolia . Test samples measuring 2.5 x 2.5 x 30.0 cm (radial x tangential x longitudinal) were placed in a pine forest stand and an open field. During a year, the samples were repeatedly weighed and evaluated by a rating system to determine mass loss and decay index, respectively. The results showed that regardless of species and type of wood, the forest environment is more favourable to decay than that of the open field. Despite the high correlation between mass loss and decay index, variations in the durability of wood were found between these parameters. The wood from the internal section of the log (sapwood) was the more affected. For mass loss, no significant variation was observed for the species analyzed, however, for the decay index Platanus x acerifolia was shown to be the most affected

VARIAÇÃO RADIAL DA MASSA ESPECÍFICA BÁSICA DA MADEIRA DE Eucalyptus grandis W. Hill ex Maiden

This study was undertaken to determine the radial variation of basic density of the wood of 14 years old Eucalyptus grandis W. Hill ex Maiden stands, located in the northern coast of Rio Grande do Sul. Thirty two trees were selected on the basis of the dominant and average diameter, and after cutting down, one disk was taken at breast height (DBH), for basic density determination in the radial direction. The results indicated that the basic density, both for dominant and average trees, presented lower values at the pith region (0,37g/cm3) increasing until the more peripheral region of the trunk (0,43g/cm3). No differences in basic density between dominant and average diameter trees were observed.Este estudo teve como objetivo verificar a variação radial da massa específica básica da madeira Eucalyptus grandis W. Hill ex Maiden, aos 14 anos de idade, proveniente de povoamentos situados próximos ao litoral norte do Rio Grande do Sul. Selecionaram-se 32 árvores com base nos diâmetros de árvores dominantes e médias, e após a derrubada, retirou-se um disco à altura do peito (DAP), destinado à determinação da massa específica básica na posição radial. Os resultados evidenciaram que a massa específica básica, tanto para árvores dominantes quanto para médias, apresentou valores mais baixos na região da medula (0,37 g/cm3), seguida de acréscimo até a região mais periférica do tronco (0,43 g/cm3). Não foram encontradas diferenças de massa específica entre madeiras de árvores médias e dominantes